DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims status
Applicants reply filed 4/8/2026 is acknowledged.
Claims 19-21, 23, 24, 26-35, 37-43 is/are currently pending with claims 29-35, 37-42 is/are withdrawn. Claims 19-21, 23, 24, 26-28, 43 is/are under examination.
Claim Interpretation - Reiterated
Claim 19 recites sequences for the reprogramming factors (RFs): Sox, Oct, KLF, Myc, Glis1, Nanog polypeptides. However the claim does not require the claimed RNA replicon to comprise each of the recited RFs rather it requires the RNA replicon to comprise at least 3 polynucleotides that encode 3 RFs. Thus, sequences for only those RFs that are required to meet the required claim limitations need to be taught by the art with other sequences being optional since they are directed to alternate and/or optional RFs.
For claim 19, RF1 is required to be either Oct4 or Sox2, RF2 is required to be Oct4 if RF1 is Sox2 or RF2 is required to be Sox2 if RF1 is OCT4. Thus, the claimed RNA replicon that requires at least 3 polynucleotides that encode RFs, 2 are Oct4 and Sox2. The claim also requires Myc or Glis1 as alternatives for the third RF i.e. RF3. Although the claimed RNA replicon may comprise additional RFs, such as Nanog, these are optional and thus not required limitations.
Claim Rejections - 35 USC § 103 - Maintained
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 19-21, 23, 24, 26, 27, 28 and 43 remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Carey et al (Reprogramming Factor Stoichiometry Influences the Epigenetic State and Biological Properties of Induced Pluripotent Stem Cells. Cell Stem Cell 9, 588–598, December 2, 2011; ref of record), Polo et al (US 2006/0292175 A1, Published Dec 28, 2006; ref of record), Lowry et al (US 20100285589 A1, Published 2010-11-11; ref of record) and P01106 (cMyc UnitProt Accession number, Sequence version available since 13-Aug-1987).
Regarding claim 19, Carey teaches polycistronic constructs comprising a combination of at least 4 reprogramming factors (Oct4, Sox2, Klf4 and cMyc) separated by various separating regions (2A peptides such as P2A, T2A, E2A and F2A as well as IRES are taught) (Figure 3A, S2D). In one of the constructs, Carey specifically teaches a combination wherein Oct4 and Sox2 precede c-Myc and the c-Myc follows a IRES separating region (OKSM construct shown in Figure 3A).
Carey shows that by altering the location of the RFs and by using different “separating regions” between the RFs, the expression level of the RFs can be altered (Figure 3A and S2D) resulting in altered stoichiometry of RFs produced. Carey shows that this alteration in stoichiometry of RFs produced affects the quality and efficiency of iPSC production (Figure 1F, 1G, 3D). The OKSM construct wherein the c-Myc RF follows a IRES separating region producing lower quality iPSCs since these iPSCs do not produce “all-iPSC” mice with as high an efficiency as the OSKM construct (Table S3, S4). With these data, Carey concludes that “The distinct factor expression levels of OSKM and OKSM reprogrammable mice strains emphasize that different factor stoichiometries can produce iPSCs but that their quality may vary” (Discussion, para 2).
Regarding claim 21, in each of the polycistronic constructs taught by Carey the first RF separating region is a 2A peptide which are self-cleaving (Figure 3A, S2D).
Taken together, Carey teaches a construct comprising sequences that encode at least Oct polypeptide, Sox polypeptide and Myc polypeptide wherein Oct and Sox encoding sequences precede Myc encoding sequence, and the sequence encoding Myc follows an IRES separating region (OKSM construct).
Although Carey teaches a polycistronic vector wherein the first two RFs are Oct4 and Sox2 (=Carey’s OSKM construct) and another polycistronic vector wherein Oct and Sox precede Myc which follows an IRES separating region (=Carey’s OKSM construct), Carey does not explicitly provide the sequences for Oct4, Sox2 and Myc or that their polycistronic constructs are within an RNA replicon vector.
The sequences for RFs taught by Carey were well-known in the art.
Lowry teaches retroviral vectors comprising KLF4, Oct4, Sox-2, Nanog and cMyc ([0004], lines 10-12, [0030], [0126]. Lowry also provides sequences for Sox2 polypeptide and polynucleotide as SEQ ID NO. 6 and 5 which are identical to instant SEQ ID NO: 6 and 5 (see Sequence alignments section below as required by claims 19, 23, 24, 43). Lowry provides sequences for Oct4 polypeptide and polynucleotide as SEQ ID NO. 4 and 3 which are identical to instant SEQ ID NO: 4 and 3 (see Sequence alignments section below; as required by claims 19, 26, 27, 43).
P01106 provides sequence from Myc polypeptide which is 99.5% identical to instant SEQ ID NO: 10 (see Sequence alignments section below; as required by claims 19).
Furthermore, Lowry also teaches the use of their vectors for reprogramming somatic cells and that RFs be delivered using any variety of vectors including non-integrating vectors when transient expression is desired [0043].
Use of RNA replicon vectors to deliver heterologous sequences was also known on the art. Polo teaches an alphavirus RNA replicon comprising in 5' to 3' order (i) a 5' sequence required for nonstructural protein-mediated amplification, (ii) a nucleotide sequence encoding alphavirus nonstructural proteins, (iii) a means for expressing a heterologous nucleic acid (e.g., a viral junction region promoter), (iv) the heterologous nucleic acid sequence (e.g., an immunogen), (v) a 3' sequence required for nonstructural protein mediated amplification, and (vi) a polyadenylate tract. Polo teaches that the RNA can comprise multiple heterologous nucleic acid sequences ([0018] and [0068]). They teach that the replicon comprises genes encoding for replicase proteins and the heterologous gene of interest ([0021); that the replicon can comprise a selectable marker ([0147]) and various promoters to express the polynucleotide sequences ([067]; [105]).
Regarding claims 20 and 28, Polo teaches that the sequences are derived from SIN and VEE [0015, as required for claim 20]. Polo teaches embodiments wherein the alpha-virus derived non-structural proteins such as the replicases, 3’UTR and poly A tail are derived from VEE ([0016], as required for clam 28). Polo also teaches the construction of a VEE derived replicon vector (Example 1, Figure 6 and 12).
Regarding claim 21, in addition to Carey’s teachings, Polo also teaches that the alpha RNA vector replicon can express one or more heterologous sequences using an IRES or promoters such as sub-genomic promoters ([068]).
Taken together, Polo teaches an alpha-virus RNA replicon comprising non-structural replicase domains from alphavirus, promoter sequences, one or more heterologous sequences, IRES as separating sequence allowing expression of more than one heterologous sequence, and 3’UTR as well as polyA sequences from alphavirus; wherein alphavirus is a VEE.
The combination of prior art cited above under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S., 82 USPQ2d 1385 (2007). Exemplary rationales that may support a conclusion of obviousness are provided in MPEP 2143.
In the present situation, rationale A- Combining Prior Art Elements According to Known Methods To Yield Predictable Results - is applicable. MPEP 2143 guides that for rationale A “Office personnel must articulate the following: (1) a finding that the prior art included each element claimed, although not necessarily in a single prior art reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference; (2) a finding that one of ordinary skill in the art could have combined the elements as claimed by known methods, and that in combination, each element merely performs the same function as it does separately; (3) a finding that one of ordinary skill in the art would have recognized that the results of the combination were predictable; and (4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness”.
In the instant case, (1) Prior art of Carey teaches the polycistronic construct that comprises the claimed elements of RFs (Oct, Sox followed by Myc) separated by separating regions; including IRES separating region preceding Myc. Lowry and P01106 provide the sequences for Carey’s RFs and Polo teaches the claimed elements of RNA replicon vectors comprising alphavirus replicases, promoter, alphavirus 3’UTR and polyA tail.
(2) Since Polo teaches the method to generate RNA replicon vectors comprising heterologous sequences, an ordinary artisan would combine the elements of Carey and Polo to produce a RNA replicon vector encoding the RFs of Carey. Furthermore, since Carey does not explicitly provide the sequences for their RFs, an ordinary artisan would overcome this deficiency by using sequences for these well-known RFs in the prior art such as from Lowry and P01106.
The combination of RNA replicon vector with RFs is not expected to alter the functioning of the expressed RF or the ability of the RNA replicon vector to function as a vector. In other words, in the combination of RNA replicon vector with RFs each element performs the same function as it does separately i.e. RNA replicon act as vector for expression of heterologous sequences such as RFs.
(3) An ordinary artisan would predict the combination of the elements of Carey, Lowry, P01106 and Polo to yield an RNA replicon vector encoding RFs wherein RFs induce pluripotency in somatic cells. Carey tests various combinations of RFs and separating regions and, shows expression of RFs under each combination. Furthermore, Carey teaches that although specifics of the combination of RFs and separating regions affects the expression levels of RFs yet each combination produces iPSCs. Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date to combine the polycistronic construct of Carey encoding RFs with a RNA replicon vector to yield a predictable result of an RNA replicon vector comprising a promoter that drives the expression of a polycistronic construct comprising at least Oct4, Sox2 and cMyc wherein cMyc follows an IRES sequence.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Regarding claim 43, this claim requires a specific combination of RFs and separating regions [(an Oct coding sequence)-(self-cleaving peptide coding sequence)-(a Sox coding sequence)-(an IRES)-(a Myc or Glis1 coding sequence)].
Carey teaches a OSKM construct wherein each of the RF is separated by a 2A peptide (figure 3A). Carey also teaches a construct comprising Oct4, Sox2 followed by cMyc (OKSM in Figure 3A) however in this construct although a 2A peptide is placed behind the Oct4, it separates Oct4 and Klf4 with both Sox2 and cMyc following an IRES sequence. Although Carey does not teach the exact arrangement of RFs and separating regions as claimed in claim 43, this rearrangement of RFs and separating regions is not expected to modify the function of the replicon or its ability to express the RFs and the ability of RFs to induce pluripotency. This is because Carey teaches that although specifics of the combination of RFs and separating regions affects the expression levels of RFs yet each combination produces iPSCs (Discussion, para 2; Table S3, S4). According to MPEP 2144.04 (VI)(C) “In re Japikse, 181 F.2d 1019, 86 USPQ 70 (CCPA 1950) (Claims to a hydraulic power press which read on the prior art except with regard to the position of the starting switch were held unpatentable because shifting the position of the starting switch would not have modified the operation of the device.)” In the instant case, rearranging the placement of RFs is not expected to affect the expression of RFs or change the function of the RNA replicon. Therefore, teachings of Carey, Polo, Lowry and P01106 as detailed above render the instant claim 43 prima facie obvious.
SEQUENCE ALIGNMENTS
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Regarding claims 19 and 23, Lowry teaches SEQ ID No. 6 as sequence for Sox-2 polypeptide that has a sequence 100% identical to instant SEQ ID NO: 6 (see alignment below).
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Regarding claim 24 and 43, Lowry teaches SEQ No. 5 as sequence for Sox-2 polynucleotide that is 100% identical to SEQ ID NO: 5 (see alignment). Although the sequence alignment is a DNA alignment, because alphaviruses are RNA viruses, the T of the DNA sequences shown will be U when using these sequences in the RNA vector.
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Regarding claims 19 and 26, Lowry teaches SEQ ID No. 4 as sequence for Oct-4 polypeptide that has a sequence 100% identical to instant SEQ ID NO: 4 (see alignment below).
Regarding claim 27 and 43, Lowry teaches SEQ No. 3 as sequence for Oct-4 polynucleotide that is 100% identical to instant SEQ ID NO: 3 (see alignment). Although the sequence alignment is a DNA alignment, because alphaviruses are RNA viruses, the T of the DNA sequences shown will be U when using these sequences in the RNA vector.
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Regarding claim 19, P01106 teaches the sequence for cMyc polypeptide that has a sequence 99.5% identical to instant SEQ ID NO: 10 (see sequence alignment below; See detailed alignment in PTO 892)
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Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 19-21, 23, 24, 26, 27, 28 and 43 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5-10, 15 and 22-23 of U.S. Patent No. 9862930. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 22-23 in ~930 recite an alpha-virus RNA replicon comprising sequences from VEE alpha-virus wherein the RNA replicon comprise each of the elements recited in instant claims 19-21, 28 and 43 (non-structural replicase domains from alphavirus/VEE, promoters, Oct (recited as RF1) followed by Sox (recited as RF3) and IRES followed by cMyc (recited as RF4), alpha virus 3’UTR and polyA tail) and encodes at least Oct-4, Sox2, and cMyc. The sequences for Oct-4, Sox2 and cMyc are provided in claims 5-10 of `930. Therefore, claims 22-23 in ~930 render obvious instant claims 20, 28 and 43 because the VEE RNA replicon of claim 22-23 encode at least Oct4 followed by Sox2 and Myc preceded by IRES as recited in the instant claims. Furthermore, the recitation of species of alphavirus in claims 22-23 (depend from claim 15 that recites VEE) renders obvious the generic alphavirus recited in instant claims 19 and 21. Furthermore, the sequences recited in instant claims 23, 24, 26, 27, 28 and 43 are taught by claims 5-10 of `930.
Response to Arguments
Applicant's arguments filed 4/28/2026 regarding U.S.C. 103 rejection of the claims 19-21, 23, 24, 26, 27, 28 and 43 have been fully considered but they are not persuasive.
Regarding Carey, Applicant state that “Carey et al. do not specifically described in the reference how their vectors are made or designed” (page 8, last para).
In response, Applicant do not identify the relevance of this statement. Applicant do not identify the requirement of a specific disclosure regarding a method of making a vector in Carey as it pertains to the instant rejection. Further, methods of making vectors were known in the art such products directed to vectors, RNA or DNA, are enabled. Carey’s vectors were known in the art such that Carey references these prior art to teach such routine methods of making that specific vectors (see references to Carey, B.W., Markoulaki, S., Beard, C., Hanna, J., and Jaenisch, R. (2010). Single-gene transgenic mouse strains for reprogramming adult somatic cells. Nat Methods 7, 56-59. and Stadtfeld, M., Apostolou, E., Akutsu, H., Fukuda, A., Follett, P., Natesan, S., Kono, T.,Shioda, T., and Hochedlinger, K. (2010a). Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells. Nature 465, 175-181.) As noted in the rejection, Polo teaches methods of making RNA replicon vectors.
Next, regarding Carey, Applicant argue that one of skill in the art would not be motivated to use construct with IRES as Carey teach that the IRES comprising vector is not “as effective” as the IRES lacking vector or did not produce robust ESC-like characteristic (page 10, para 1, 2)
In response, indeed as noted in the instant rejection, “The OKSM construct wherein the c-Myc RF follows a IRES separating region producing lower quality iPSCs since these iPSCs do not produce “all-iPSC” mice with as high an efficiency as the OSKM construct (Table S3, S4). With these data, Carey concludes that “The distinct factor expression levels of OSKM and OKSM reprogrammable mice strains emphasize that different factor stoichiometries can produce iPSCs but that their quality may vary” (Discussion, para 2).” Thus, Carey teaches that although specifics of the combination of RFs and separating regions affects the expression levels of RFs yet each combination produces iPSCs. According to MPEP 2123, “In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use."
Next, regarding Carey, Applicant argue “As clearly described in Applicant's invention the integration of DNA vectors (such as those taught by Carey et al.) are not suitable due to integrative mutations that may occur” (page 10, para 2).
In response, it is unclear what Carey’s vector is unsuitable for. Furthermore, Carey is not relied upon for the teachings pertaining to RNA replicon. There is no requirement that teachings regarding the use of RNA replicon vectors be present in Carey. Elements pertaining to the structural elements of an RNA replicon vector that could be used to express Carey’s construct are taught by Polo. As noted in the rejection, Polo provides the teachings for using an RNA replicon to express heterologous sequences. Polo states that “For purposes of the present invention, virtually any polypeptide or polynucleotide can be used” [0156]. This is reasonable since Polo’s disclosure provides an alternative vector system. An ordinary artisan routinely uses various vector systems to express polypeptides of interest. For example, prior art had delivered the Yamanaka reprogramming factors (i.e. Oct4, Sox2, Klf4, cMyc) using various vector systems to generate iPSCs (Carey uses lentivirus, Lowry uses retrovirus, Hochedlinger (WO 2011/109612 A1, 9 September 2011; IDS 9/18/2020, [0158]) uses plasmids).
Regarding Polo, Applicant state that “Polo et al. teach chimeric alpha virus particles, preparation of such alphaviruses and uses for administration of heterologous genes (see, abstract and ¶0003)” (page 11, para 1) and in “the description in Polo et al. of "heterologous sequence(s)" does not necessarily mean a polycistronic construct. In other words, a construct may have multiple sequences, but does not result in "a single mRNA encoding multiple distinct proteins from a single transcript." Thus, Applicant submits that the Examiner has misconstrued the terminology of Polo et al. and read into Polo et al. the term "polycistronic" when in fact, the term "polycistronic" does not appear once in Polo et al.” (page 12, para 1). Applicant also argue that “Polo et al do not teach or suggest the Reprogramming factors recited in Applicant's claim 1. Moreover, Polo et al. do not teach or suggest that the heterologous nucleic acids can be separated by other than an IRES or wherein the last of the separating regions is an IRES, which the others are optionally IRES's, promoters or self-cleaving peptides coding sequences” (page 12, para 2).
In response, the arguments are identical to the arguments presented in the response filed 9/25/2026 (pages 10-12) and were addressed in the OA dated 1/28/2026 (pages 21-22).
The response was as follows:
“indeed Polo, like most art, has several teachings including the one pointed to by the Applicant and also the teachings regarding the components of a RNA replicon vector that are relevant for the instant claims. As is evident from the text quoted from Polo by the Applicant, Polo explicitly teaches “The alphavirus RNA vector replicon also should contain a means to express one or more heterologous sequence(s), such as for example, an IRES or a viral (e.g., alphaviral) subgenomic promoter” [068]. This teaching is inherently directed to a polycistronic construct as defined by the Applicant i.e. “"a single mRNA encoding multiple distinct proteins from a single transcript”. This is because the teaching from Polo quoted above is directed to the (=a) alphavirus RNA vector replicon (=mRNA) for expressing one or more heterologous sequence(s) (=encoding multiple distinct proteins from a single transcript). This is further evident from description in Polo regarding IRES, which is a regulatory element used to separate mRNA sequences that encode different polypeptides within a single mRNA transcript and allows for separate translation of these sequences even though they are part of one mRNA. Thus, the description in Polo et al. of "heterologous sequence(s)" necessarily means a polycistronic construct.
Additionally, as noted in the rejection of record, Polo teaches “that the alpha RNA vector replicon can express one or more heterologous sequences using an IRES or promoters such as sub-genomic promoters ([068])”. Elements pertaining to the structural elements of the construct, such as RFS, 2A peptides and IRES, that could be expressed using Polo’s vector are taught by Carey.”
Regarding the combination of Carey and Polo, Applicant argue that “although Carey et al. teach a polycistronic DNA vector there is no evidence that one of skill in the art could generate a polycistronic alpha-virus RNA vector based upon the teachings of Polo et al. Moreover, even if there was some suggestion of success, one of skill in the art would recognize that there is no reasonable expectation of success in an RNA construct containing an IRES as Carey et al. expressly indicates that the IRES construct (even when DNA) does not provide a robust ESC-like induced stem cell.” (page 13, para 1)
In response, Carey describes the expression of RFs from a polycistronic construct, albeit not a RNA replicon (Figure 3A). Polo teaches RNA replicons and their utility in expressing heterologous genes, including in a polycistronic construct ([0018], [0068]). Polo provides ample teachings regarding making RNA replicon constructs (Example 1) and alphavirus replicon particles (Example 3). Polo uses routine molecular biology techniques such as restriction digestion, oligo ligation, insertion of desired oligo fragments at desired sites in a construct and indicate such teachings as “commonly employed” [0167]. Thus, contrary to Applicant’s allegation, ordinary artisan in the field of molecular biology could generate a polycistronic alpha-virus RNA vector based upon the teachings of Polo and Carey.
Furthermore, Carey does not teach that constructs comprising IRES do not generate iPSC. They merely teach that the IRES comprising constructs are less efficient. Relevant to the instant claims, the ability of specific RFs to predictably reprogram cells into PSCs has been well known since the pioneering work of Takahashi and Yamanaka (see Introduction in Schmidt et al, ref of record). Prior art has delivered the Yamanaka factors (i.e. Oct4, Sox2, Klf4, cMyc) using various vector systems to generate iPSCs (Carey uses lentivirus, Lowry uses retrovirus, Hochedlinger (WO 2011/109612 A1, 9 September 2011; IDS 9/18/2020, [0158]) uses plasmids). Considering that RFs delivered via different vector system each generated iPSC, the reasonable expectation was that RNA replicons would as well.
Regarding Lowry, Applicant state “The Examiner's asserts that Lowry et al. teach retroviral vectors comprising reprogramming factors. Applicant submits that alphaviruses are not retroviruses. Retroviruses insert a DNA copy of its RNA genome into the DNA of a host cell that it invades. In contrast, alphaviruses do not integrate into the host's genome. Retroviral vectors, as taught by Lowry et al. 'integrate' into the host's DNA genome (cumulative to Carey et al.) (page 13, para 2).
In response, the arguments are identical to the arguments presented in the response filed 9/25/2026 (pages 13) and were addressed in the OA dated 1/28/2026 (pages 24-25).
The response was as follows:
“no assertion in the rejection of record was made wherein Lowry’s vector was suggested to be the same as a RNA replicon. Similarly, no such assertion is made in the instant rejection. Elements pertaining to the structural elements of an RNA replicon vector that could be used to express Carey’s construct using Lowry’s sequences are taught by Polo”.
Next, regarding Lowry, Applicant argue that since “Lowry et al. teach standard retroviral vectors and herpes viruses (e.g., Epstein Barr Virus)” and do not contemplate alpha viruses and, the most commonly used non-integrating vector is AAV “One of skill reading Lowry et al. would contemplate using adeno-associated viral vectors (AAVs), which is the most commonly used non-integrating vector” (page 14, para 1).
In response, the arguments are identical to the arguments presented in the response filed 9/25/2026 (pages 14) and were addressed in the OA dated 1/28/2026 (page 25).
The response was as follows:
“there is no evidence that an artisan, especially a skilled artisan, would limit themselves to only an AAV or only a “most common” vector. Carey, Polo and Lowry are each prior art available to an artisan that were capable of combining them based on common molecular biology techniques, also taught in each of these prior art.”
Next, regarding Lowry, Applicant argue that “Lowry et al. do not teach or suggest alphavirus replicons and thus is directed to a totally different type of delivery system. Moreover, Lowry et al. do not teach or suggest multiple heterologous reprogramming factors separated by a separating sequences wherein the last RF is proceeded by an IRES” (page 14, para 2).
In response, the arguments are identical to the arguments presented in the response filed 9/25/2026 (pages 14) and were addressed in the OA dated 1/28/2026 (page 25).
The response was as follows:
“the elements pertaining to RFs and separating regions, including IRES preceding last RF, is taught by Carey. Lowry is relied upon to provide the sequences for the RFs.”
Finally, regarding the combination of Carey, Polo and Lowry, Applicant argue that “One of skill in the art would not arrive at a polycistronic RNA vector with a tailing IRES because (i) there is no reasonable expectation of success that a polycistronic RNA vector would work and (ii) there is an indication that any such polycistronic RNA vector with an IRES would not work effectively. Adding Lowry et al. (which is cumulative to Carey et al.), one would still not arrive at a polycistronic RNA with a tailing IRES. Importantly, even if one were to chop and redesign (i.e., invent) a polycistronic RNA as asserted by the Examiner, there is no reasonable expectation of success that such a construct would reprogram cells as taught by Applicant's disclosure, because Carey et al. teach that even when more stable vector constructs are used (e.g., DNA vectors), such polycistronic DNAs with an IRES are not as effective.” (page 14, para 3).
In response, as detailed above, arguments pertaining to (i) and (ii) above were not persuasive. Argument pertaining to stability of DNA vectors is unclear. It appears that the Applicant is arguing that RNA replicon vectors are unstable. Polo teaches that RNA replicon vectors are used for expression of heterologous sequences thus RNA replicon vectors are known to function as vectors that lead transgene expression. Regarding the expectation of the RNA replicon construct with RF factors, as taught by Carey, Lowry and Polo, to reprogram cells, RFs have been delivered in various combinations and using varied vector systems resulting in cell reprogramming (see Carey, Lowry, Hochedlinger). Thus, the reasonable expectation was the RNA replicons also delivering RFs would result in reprogramming.
Of note, the specification does not generate a RNA replicon construct wherein the first two RFs are Oct4 or Sox2 followed by IRES followed by cMyc (Figure 1A shows all the constructs). Similar to Carey, Applicant also produce a OKSM construct i.e. Oct4-Klf4-Sox2- IRES-cMyc.
Applicant’s arguments with respect to the NSDP rejection of claim(s) 19-28 and 43 over US Patent 9862930 have been considered but are not persuasive. Applicant requests the rejections be held in abeyance (page 15, para 2).
In response, the request is acknowledged but the rejection is maintained till a persuasive argument(s) or a properly filed TD is on file (See MPEP1207.02).
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATASHA DHAR whose telephone number is (571)272-1680. The examiner can normally be reached M-F 8am-4pm (EST).
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/MATASHA DHAR/Examiner, Art Unit 1632
/EMILY A CORDAS/Primary Examiner, Art Unit 1632
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